We propose to separate from the serum of normal individuals a protease inhibitor termed C1 inhibitor, a glycoprotein which inhibits enzymes of the complement, kinin-forming coagulation and fibrinolytic systems. We will apply to this protein classical chemical procedures to obtain peptides that will separate from one another either by ion-exchange chromatography or a combination of high voltage electrophoresis and partition chromatography. Following this, we plan to apply identical conditions to obtain peptides derived from dysfunctional C1 inhibitor representing various genetic variants in patients with hereditary angioneurotic edema. Comparison of the structures of the non-common peptides of normal and nonfunctional C1 inhibitor should define the chemical basis for this genetic abnormality and locate the reactive site residues of C1 inhibitor. This hypothesis will be further tested by determining the chemical nature of the interaction of C1 inhibitor, dysfunctional C1 inhibitor and the proposed reactive site peptides with C1s and other human proteolytic enzymes with which C1 inhibitor has been shown to react.